CN109862882A - For treating the method and composition of dermatophytid infection - Google Patents

For treating the method and composition of dermatophytid infection Download PDF

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Publication number
CN109862882A
CN109862882A CN201780066597.1A CN201780066597A CN109862882A CN 109862882 A CN109862882 A CN 109862882A CN 201780066597 A CN201780066597 A CN 201780066597A CN 109862882 A CN109862882 A CN 109862882A
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solution
antifungal agent
antiperspirant
treatment
terbinafine
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卡尔·F·尚巴赫
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A61K8/26—Aluminium; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/0208—Tissues; Wipes; Patches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • A61K8/0216—Solid or semisolid forms
    • A61K8/022—Powders; Compacted Powders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/34—Alcohols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q15/00—Anti-perspirants or body deodorants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
    • A61K2800/87—Application Devices; Containers; Packaging

Abstract

The present invention relates to the method and compositions for treating dermatophyte illness such as tinea pedis.Such illness can be in progress through multiple stages such as fungi stage and bacterium stage, make it difficult to realize effective treatment results.The present invention relates to the combination treatment that one kind effectively treats the illness, which realizes beneficial therapeutic effect using the balance combination of daily administration antifungal agent, antiperspirant and desiccant, and how is disease stage when starting but regardless for the treatment of.

Description

For treating the method and composition of dermatophytid infection
Related application
This application claims the equity for the U.S. Provisional Patent Application Serial No. 62/380,787 submitted for 29th in August in 2016, Content is hereby incorporated by reference in its entirety.
Invention field
The present invention relates generally to the composition and method for the treatment of dermatophytid infection, the dermatophytid infection includes foot Tinea, ringworm of the body and jock itch.
Background
Until in the 1940s, for tinea pedis (tinea pedis) almost without any treatment.During the war of mid-twentieth century, Due to the stimulation of dermatomycosis prevalence in army personnel, it is sought for really effective treatment.Azole antifungal agent is in 20 generation The discipline later period sixties synthesizes for the first time, and in next 20 years, and research and development concentrates on this kind for the treatment of, represents fungi sense Important breakthrough in the targeted therapy of dye.In the 1990s, the exploitation of effective fungicidal allylamines achieves further Progress.Today, a kind of such allylamine, Terbinafine is still the most effective treatment of tinea infection.Terbinafine is resistant to Most effective topical agent (Crawford & Hollis, the Cochrane Database of Systematic of tinea pedis Reviews 2007, Issue 3. Art. No.: CD001434).It is different from the fungistat for needing to apply up to surrounding, Terbinafine is effective in shorter treatment process.The label guide of terbinafine emulsifiable paste requires twice daily to apply at present 1-2 weeks (Lamisil AT Drug Facts, GlaxoSmithKline Consumer Healthcare Holdings, 2017)。
In contrast, the antiperspirant treatment of tinea pedis is paid close attention to by the science of relative rarity.Antiperspirant treatment to tinea pedis The researchs in 1975 from Leyden Kligman of unique noticeable example (Arch Dermatol, volume 111, Page 1004, in August, 1975).They have found that 30% liquor alumini chloridi effectively reduces the malaise symptoms of tinea pedis.However, this treatment It is not fully solved infection；But it will it is relevant to bacterium coinfection (sometimes referred to as dermatomycosis complex) macerate, The tinea pedis of stench form becomes dry Palta type again, this indicates pure fungal infection (pure dermatomycosis).Due to right Be expected to treatment tinea pedis basic reason antifungal agent exploitation concern, for antiperspirant treatment tinea pedis in purposes rarely have into One step research.2001, Koca et al. (O.M. ü Tip Dergisi Cilt:18 No. 3, page 192,2001) into One has been gone about the research of antiperspirant-antifungal agent combination treatment.Patient is instructed to apply in the morning (a kind of containing clotrimazole The azole antifungal agent of restraining epiphyte) emulsifiable paste, and at night apply chlorination hydroxyl aluminium emulsifiable paste.It was discovered by researchers that with individually anti- Fungi agent therapy is compared, and antiperspirant is added and is no advantage.
Dees (U.S. Patent number 7,201,914) description is used for antiperspirant and antimicrobial combination to treat acne. Dees does not describe example of the topical antifungal agents as antimicrobial of any standard.Lester (U.S. Patent Publication No. 2010/0056430) description antibacterial agent reduces foot odour with other compositions such as Terbinafine and aluminium chloride, but Lester does not have Have to combine his material with alcohol desiccant or combine them and is used to treat infection, such as dermatomycosis.Villalobos (U.S. Patent Publication 2012/0061267) description uses the Terbinafine cleaning piece with alcohol.Villalobos is simultaneously not used anti- Microbial inoculum or antiperspirant compound, and effect is not proved.
What is desired is that a kind of effective therapy can apply regardless of the stage infected for effectively treating skin Skin fungal infection.
Summary of the invention
A problem in the prior art is that previous composition has ignored antiperspirant and can have to Symptomatic fungal infection is treated Some positive influences.In addition, having not been recognized that the benefit for combining suitable antiperspirant with suitable antifungal agent and institute The synergistic effect obtained provides the therapeutic effect accelerated.In addition, appropriate treatment medium cannot be underestimated to patient compliance and treatment Successful importance.
The present invention relates to the groups that tinea pedis He other fungal infections (such as jock itch) are treated comprising antifungal agent and antiperspirant Close object and method.Antifungal agent and antiperspirant are complimentary to one another, and provide than itself any obvious preferably treatment.
A preferred embodiment of the invention includes antifungal agent, antiperspirant, solvent and the medium for solution delivering Combination.Antiperspirant (Aluminium chloride hexahydrate) and solvent (hydrous ethanol) synergistically act on: antiperspirant reduces sweat and solvent makes Skin dehydration forms dry environment, this makes fungi and bacterium be more difficult to grow.The activity supplement antifungal agent to the effect of fungi with And the antibacterial properties of antiperspirant and solvent.
Composition of the invention is more more effective than previous composition in terms for the treatment of tinea pedis, and overcomes for treating tinea pedis Existing conventional method defect.
In one aspect, the present invention includes a kind of method for treating dermatophytid infection.This method may include following Step: part applies antifungal agent, local to apply the antiperspirant comprising aluminium salt, and part applies the solvent medium comprising alcohol, wherein The antifungal agent, antiperspirant and solvent medium all apply during single administration event and repetitive administration event is no more than About once a day.
Embodiment of the present invention includes using antifungal antifungal agent, and the fungicide can be allylamine. Suitable fungicide is Terbinafine or its pharmaceutically acceptable salt.In some embodiments, antifungal agent is to include At least one of Amorolfine, Butenafine, Naftifine, Terbinafine or Tolnaftate or its pharmaceutically acceptable salt kill Epiphyte pharmaceutical.Preferably, this method is repeated until infection solves, and KOH (potassium hydroxide) microscope test fungi can be used In the presence of come the solution that determines infection.
In some embodiments, the antiperspirant of this method is Aluminium chloride hexahydrate or comprising Aluminium chloride hexahydrate.Solvent Medium may include ethyl alcohol or ethyl alcohol (ethyl alcohol).The duration ranges for the treatment of can be 1-4 weeks, such as depending on treatment Effect.Daily administration is preferably as this can prevent the over-drying for the treatment of region.Other antifungal agents can be used for this hair It is bright.Therefore, this method may include using following antifungal agent: azole, including clotrimazole, ketoconazole, Fluconazole, Flutrimazole, Econazole, bifonazole, butoconazole, econazole, Fenticonazole, Isoconazole, luliconazole, Miconazole, Omoconazole, former times difficult to understand Health azoles, Sertaconazole, sulconazole, tioconazole, thiabendazolum, croconazole, benzyl chloride up to azoles, Neticonazole, terconazole, posaconazole, At least one of voriconazole, albaconazole, Chinese mugwort Saperconazole, Eberconazole or Chinese mugwort Fluconazole；Or polyenoid, including anphotericin B, at least one of nystatin, Hamycin and natamycin；Or nystatin, natamycin, trichomycin, pecilocin, beauty Partricin, pyrrolnitrin, griseofulvin, Bromosalicylchloranilide, methylrosaniline, tribromometacresol (tribromometacresol), undecenoic acid, polynoxylin, 2- (4- chlorophenoxy)-ethyl alcohol, Chlorphenesin, replace carat Ketone, Afungin, ethyl-para-hydroxybenzoate, Haloprogin, selenium sulfide, Ciclopirox Olamine, dimazole, Flucytosine, benzene are pricked Oronain, benzoyl peroxide, benzoic acid, salicylic acid, tannic acid, boric acid, gentian violet, Chlorhexidine, cetylpyridinium chloride, Tosi Draw ester, sodium thiosulfate, potassium iodide, tea oil, citronella oil, lemongrass oil, garlic, vinegar, he cut down boron sieve (tavaborole), Ah Ba Fen is net, echinocandin (Caspofungin, mikafen and anidulafungin), Nikemycin, pradimicin (pradimicin) or At least one of Bei Nanuo mycin；Or its pharmaceutically acceptable salt.
Another aspect of the present invention relates to the composition for treating dermatophytid infection, the composition includes: anti-true Microbial inoculum, the hidroschesis desiccant comprising aluminium salt, and the solvent medium without emulsifiable paste, the solvent medium include alcohol, anti-true for delivering Microbial inoculum and desiccant.Antifungal agent is preferably fungicide, can be Terbinafine or its pharmaceutically acceptable salt.
Composition of the invention further includes fungicide comprising at least one of the following: Amorolfine, Butenafine Sweet smell, Naftifine, Terbinafine or Tolnaftate or its pharmaceutically acceptable salt.The composition can be via cleaning piece or " small Mao Towel (towlette) " application, such as applied from sealing, disposable, peelable packaging or packet.One disposable wipe Packet can be opened and be used daily to effectively treat illness, and at second day using second packet etc., until infection solves.This is controlled About one week (for example,/seven applications of seven packets) may only be needed by treating the duration, or for certain situations, it may be necessary to two to four The treatment (once a day) in week.
Composition of the invention includes with Terbinafine existing for the amount of the 0.5-10% of composition weight.Aluminium salt (for example, Aluminium chloride hexahydrate) can exist with the amount for being no more than (composition) weight about 30%.In some embodiments, aluminium salt amount It reduces to about 15 to 20 weight %.Preferred antiperspirant is Aluminium chloride hexahydrate (AlCl3•6H2O)。
Another aspect of the present invention includes the solution for treating dermatophytid infection, can be generated by following procedure. Terbinafine (or its pharmaceutically acceptable salt) is added in liquid solvent solution, the liquid solvent solution be ethyl alcohol or Including ethyl alcohol.By aluminium chloride (such as the AlCl of crushing through measurement amount3•6H2O) be added in solution, then by solution for example with The Terbinafine that other ethyl alcohol supplement rises solution at the concentration of aluminum chloride of about 200 grams per liters (gm/ liter) solution and about 10gm/ is dense Degree.Preferably, Terbinafine and AlCl3 are thoroughly dissolved to generate uniform solution.Solution can be added in cleaning piece For finally treating patient, such as dermatophyte illness.As described above, cleaning piece can store in packet.
Embodiment includes that solution is produced using Terbinafine, and Terbinafine is provided as powder, and additional amount can not More than about 100gm/ liter.Embodiment further includes having AlCl3 with the amount that no more than about 300gm/ rises solution.
Another aspect of the present invention includes embodying kit of the invention.The kit may include product or container, institute State product or container include: antiperspirant, the antiperspirant include can the amount that rises of about 200gm/ be dissolved in alcoholic solvent (such as comprising alcohol The solvent of (such as ethyl alcohol)) aluminium salt；Dissolve in the fungicide in solution；And alcoholic solvent.It can be by fungicide and antiperspirant It is dissolved in alcoholic solvent to form solution, and container is used to accommodate product.
In the embodiment of kit, fungicide includes orolfin (Amorolfine), Butenafine, Naftifine, spy Or Tolnaftate or its pharmaceutically acceptable salt at least one of more fragrant than naphthalene.The kit may also include applicator, such as wipe Wipe object and/or spin.In some embodiments, the kit includes the cleaning piece that at least seven is used to apply solution, and every A cleaning piece can be packed individually, such as using daily.The kit can also include calendar and/or instruction set, the day Go through the daily administration for the treatment that the material for tracking kit is used.
It is described in detail
Although verified antifungal agent is that effectively, they are treating the clinical effect in tinea pedis in terms of the ability for eliminating fungi Fruit not impressive.In many cases, tinea pedis is not only fungal infection between toe, and therefore to independent antifungal agent For be more difficult to solve.Hypha,hyphae permeates cuticula, weakens it, and therefore weakens defence of the skin to further infecting.Very Bacterium also generates penicillin and streptomysin sample substance.In this environment, the bacterial multiplication of penicillin resistant generates protolysate Matter decomposes the tissue of skin between toe, leads to soaking and leukokeratosis.These bacteriums also generate sulphur compound, and sulphur compound is Effective natural antifungal agent.In these cases, bacterium coinfection can actually eliminate primary fungal infection；However, Since the cuticula in gap has been weakened and bacterium infection has been taken root, in the case where fungi is not present, bacterium infection continues In the presence of prevention cuticula heals.In this stage of disease, individual antifungal therapy effect is limited, because bacterium infection is As main problem.
These tinea pedis cases may not represented obviously sufficiently in clinical test.Since bacterium has naturally antimycotic Effect has reached the serious tinea pedis case usually potassium hydroxide to fungal infection for identification and the training in complicated coinfection stage Feeding test provides negative findings.It is estimated that fungi can have recovery (Leyden, J in symptom gap in as low as one third Am Acad Dermatol, volume 31, the 3rd phase, part 2,1994, the S31 pages).However, common in the twentieth century second half The clinical test for testing antifungal drug effect almost always need with two kinds of tests confirmation fungal infections.This means that In these researchs, the tinea pedis patient that disease has proceeded to the point of bacterium superinfection is not represented sufficiently, because infection is tight Principal characteristic leads to not the presence of fungi in exact p-value.Therefore, the research for being absorbed in antifungal efficacy may over-evaluate facing for drug Bed validity, because not including the tinea pedis patient of signal portion, and these patients are less likely effectively treatment with antifungal agent Especially uncomfortable tinea pedis form.
Antifungal agent and antiperspirant are resistant to tinea pedis and two kinds of weapons effectively with complementation of other dermatophytid infections.It is anti- Epiphyte pharmaceutical is designed to by destroying organism (fungicide) or by preventing further fungi growth (mycostasis) Fungi is eliminated, so that the skin is got rid of fungi as time go on.Antiperspirant can supplement the effect of antifungal agent in two ways: By dry skin and by killing bacterium.Antiperspirant can dry skin in two ways: firstly, passing through precipitating obstruction sweat gland Plug, prevent moisture reach skin；With secondly, leading to tissue contracts by serving as astringent, this can reduce skin and keep water Ability and diminution pore.Fungi and bacterium can all grow up strong and sturdy in moist environment such as foot (especially space between toe), therefore It is significant for reducing the benefit of moisture.In fact, epidemiologist have been found that the shoes of occlusion be the most important risk of tinea pedis because One of element provides ideal environment because it captures the heat and moisture around foot for microorganism growth.
The beneficial aspect of second of antiperspirant based on aluminium is their antibacterial activity.Have shown that the antiperspirant based on aluminium With in vitro and in vivo antibacterial action, show anti-microbial effect of the successful antibacterial action independent of dry skin.It is this Antibacterial action is for supplementing desiccation；However, it is believed that desiccation is that this treatment is made to be effective against the main of tinea pedis Mechanism.For example, Leyden & Kligman has found chlorination hydroxyl aluminium (one at them in research of the aluminium salt as tinea pedis treating object Kind of effective antibacterial agent but invalid astringent) effect not as good as aluminium chloride (antibiotic property lower but better astringency), shows to reduce Moisture rather than antibacterial activity are the main mechanisms that antiperspirant alleviates tinea pedis symptom by it.
It is nearest research and propose the effect perspired in tinea pedis and other dermatomycosis may be than being understood in the past more A possibility that important.Connection between several research discoveries sole ephidrosis (foot excessive sweating) and tinea pedis.Researcher is general Assuming that unidirectional causality, i.e., the tinea pedis developing risk with the patient for both depositing ephidrosis is bigger.However, recently to nest shape angle The loosen research of disease (bacterium infection of foot) of matter shows that ephidrosis is caused by infection strongly, rather than opposite (Pranteda Et al., Dermatologic Therapy, volume 27, page 101,2014).Inflammatory reaction of author's inference skin to infection Sweat gland function is promoted to enhance.Seem that likely similar dynamics plays a role in dermatomycosis.The model will indicate Vicious circle is perspired wherein infection increases, and the creation infection of this excess water becomes condition that is deep-rooted and aggravating.If Really this dynamics occurs, it will reinforce effect of the antiperspirant in successful treatment tinea pedis, emphasize that wet environment is sent out in infection Importance in exhibition.
The present invention relates to comprising antifungal agent, antiperspirant and medium to treat tinea pedis and other fungal infections such as jock itch Composition.Antifungal agent and antiperspirant it is complimentary to one another and provide than any obvious better treatment that can be provided separately.Only Sweat agent supplements the effect of antifungal agent in two ways: by dry skin and killing bacterium.It is noted however, that preventing from controlling Skin is over-drying during treatment, this may cause a series of problems of its own.The present invention is directed to reduce due to caused by perspiring Excess water then will lead to skin exsiccation but if excessively continually applying, some symptoms of this aggravation tinea pedis, including erythema And furfur.In addition, once infection solves, and it is over-drying to prevent skin healing, cause to stop once treating, skin just holds Vulnerable to new infection.As detailed below, application desiccant no more than once seems especially effectively daily.Medium can supplement activity The activity of ingredient.Due to the antibacterial properties of antiperspirant (and some media), composition of the invention provides anti-better than being used alone Epiphyte pharmaceutical treats the advantages of tinea pedis, because many tinea pedis cases are related to bacterium coinfection.The present invention, which also helps, resists fungi sense Dye, because the desiccation of antiperspirant and alcohol medium is unfavorable for fungi growth.Appropriate selection antifungal agent (such as fungicide), Antiperspirant and dry solvent medium can produce no matter how infective stage is all to the treatment effective composition of dermatophyte illness.
Antimycotic component
Antifungal agent is the drug for selectively eliminating fungal pathogens, has the minimum toxicity to host.The existing of tinea pedis resists Fungi therapy can be locally or systemically form.Systemic therapy is related to hepatotoxicity wind agitation risk；Therefore, local treatment is due to its safety Overview is usually preferred, and systemic therapy is carried out in the case where local treatment is invalid.Typically pharmaceutical admixtures are usually 1-4 weeks.The specific function of different types of antifungal agent targeting fungal cell.
For the most common antifungal agent by interfering ergosterol to work, ergosterol is of the utmost importance group of fungal cell membrane Point.Polyenoid is to develop to treat the first drug of fungal infection, it forms channel, small molecule directly in conjunction with ergosterol It can be oozed out from cell by the channel, lead to cell death.The drug for belonging to such includes amphotericin B, and nystatin is breathed out Mycin and natamycin.The shortcomings that polyenoid is their toxicity: they tend in conjunction with other sterol, solid including the gallbladder in human body Alcohol.Today, they are mainly used as the local treatment of confrontation Candida species.
Successful azole antifungal agent extensively is obtained first, is acted as and in conjunction with 14 α of enzyme lanosterol-demethyl enzyme With 14 α of lanosterol-demethyl enzyme is to convert lanosterol to necessary to ergosterol.Ergosterol cannot be generated Fungal cell is not able to maintain complete and breeding, and from skin exfoliation.This is a kind of restraining epiphyte mechanism, it is meant that fungi growth by Resistance, but fungi will not be killed immediately, but, patient has to wait for the cuticula that skin gets rid of its infection.This means that using azoles Class treatment usually requires longer therapeutic scheme (being in many cases surrounding) and strictly observes.Well-known azole includes Clotrimazole, ketoconazole, Fluconazole, Flutrimazole, econazole, bifonazole, butoconazole, econazole, Fenticonazole, different health Azoles, luliconazole, Miconazole, Omoconazole, Oxiconazole, Sertaconazole, sulconazole, tioconazole, thiabendazolum, croconazole, Benzyl chloride reaches azoles, and Neticonazole, terconazole, posaconazole, voriconazole, albaconazole, end Saperconazole, Eberconazole and Ai Fukang Azoles.
Different from restraining epiphyte azole, allylamine antifungal agent is mainly antifungal.These compounds inhibit different enzymes, Squalene epoxidase, this is the essential part of the early stage of ergosterol biosynthesis.As azole, this leads to etembonate Alcohol lacks；However, allylamine also results in toxicity accumulation of the squalene in cell, lead to faster cell death.Allylamine Fungicidal action allows shorter and more effective therapy: even if they are also possible to effectively in single dose, and in short treatment Recurrence is less likely to be visible after process.The allylamine of local application includes Amorolfine, Butenafine, Naftifine and Te Bi naphthalene It is fragrant.From the 1990s since, Terbinafine has become the selection drug of most of tinea pedis cases, this is in very great Cheng It is because its shorter therapeutic scheme causes to improve compliance rate on degree.The preferred embodiments of the invention use fungicide, and Especially allylamine.It has been found that Terbinafine is especially effective.
Tolnaftate is a kind of thiocarbamate of synthesis for being frequently used for treatment tinea pedis.Its exact mechanism of action is still It imperfectly understands, it is believed that the function of Tolnaftate interference squalene epoxidase, quite as allylamine.
Other chemical reagent are used as antifungal agent, including nystatin, natamycin, trichomycin, pecilocin, U.S. pa song Star, pyrrolnitrin, griseofulvin, Bromosalicylchloranilide, methylrosaniline, tribromometacresol, undecenoic acid, polynoxylin, 2- (4- chlorophenoxy)-ethyl alcohol, Chlorphenesin, Ticlatone, Afungin, ethyl-para-hydroxybenzoate, Haloprogin, sulphur Change selenium, Ciclopirox Olamine, dimazole, Flucytosine, benzalkonium chloride, benzoyl peroxide, benzoic acid, salicylic acid, tannic acid, boric acid, Gentian violet, Chlorhexidine, cetylpyridinium chloride, tolciclate, sodium thiosulfate and potassium iodide.Natural drug also serves as anti- Epiphyte pharmaceutical, tea oil, citronella oil, lemongrass oil, garlic and vinegar.Finally, novel agent for example he cut down boron sieve, Abafungin, spine ball Bai Su (Caspofungin, mikafen and anidulafungin), Nikemycin, pradimicin and Bei Nanuo mycin is provable can be used for controlling Treat fungal infection, including tinea pedis.
Embodiment of the present invention may include any antimycotic component listed above.Preferred embodiment utilizes special ratio Naphthalene is fragrant, currently available most effective antifungal agent.
Antiperspirant component
All compounds by FDA approval for over the counter antiperspirant are all aluminium salts, enjoy the Common Mechanism for reducing sweat.Aluminium salt It is worked by blocking remote sudoriferous duct.They are compound with sweat duct keratin and mucopolysaccharide, destroy sweat duct cuboid cell lining And polymer gel shape casting (cast) is formed, block sweat channel.The generation of sweat is not turned off；Conversely, there exist in Sweat gland in reticular corium and adipose tissue continues to generate sweat, although due to blocking via the aluminium salt compound in the sweat duct of distal end Normal exit approach, yield substantially reduce.Have been noted that the secretion spiral that aluminium salt plug can extend downwardly into adipose tissue In.In the case where applying aluminium antiperspirant for a long time, the secretory cell in sweat gland is often damaged, and sweat is caused to generate reduction.With Casting finally decomposes, and sweat generation eventually restores.
In some embodiments of the present invention, antiperspirant component can be aluminium chloride, chlorination hydroxyl aluminium, the poly- second of chlorination hydroxyl aluminium Two alcohol complexs, chlorination hydroxyl aluminium propylene glycol complex compound, dichloride hydroxyl aluminium, dichloride hydroxyl aluminium polyethylene glycol complex compound, dichloride hydroxyl Aluminium propylene glycol complex compound, sesquialter chlorination hydroxyl aluminium, sesquialter chlorination hydroxyl aluminium polyethylene glycol complex compound, the complexing of sesquialter chlorination hydroxyl aluminium propylene glycol Object, the aluminum sulfate of buffering, eight chlorine hydroxyl aluminium zirconiums, eight chlorine hydroxyl aluminium zirconium glycine complexes, pentachloro- hydroxyl aluminium zirconium, pentachloro- hydroxyl aluminium zirconium glycine Complex compound, aluminum zirconium tetrachlorohydrate, aluminum zirconium tetrachlorohydrate glycine complexes, trichlorine hydroxyl aluminium zirconium or trichlorine hydroxyl aluminium zirconium glycine complexes. Due to the worry for the health effect that the public takes in aluminium, non-aluminum antiperspirant be commercially also it is desired, although they are usually Not as good as the effective antiperspirant of aluminium salt.The example of non-aluminum antiperspirant includes peptide, methenamine, tannin and other astringents and titanium Salt.The present invention pays close attention to the antiperspirant based on aluminium, this is because the tracing record for the effect of they are proved and current science are recognized Know, i.e., it is unrelated with increased risk of cancer or other negative health effects based on the antiperspirant of aluminium.
In a preferred embodiment, antiperspirant is Aluminium chloride hexahydrate (AlCl3 6H2O) --- hydrated form Aluminium chloride.Aluminium chloride hexahydrate is usually used in water, aqueous alcohol or absolute alcohol with the concentration of 10-30%.Higher concentration is to skin The irritation of skin is bigger.Aluminium chloride hexahydrate also has the convergence and anti-microbial properties of composition for use in the present invention.
Medium
Medium is used to active constituent (antifungal agent and antiperspirant) being delivered to skin.Medium be can choose to enhance or supplement work The quality of property ingredient.In the present invention, it is preferred to the medium based on alcohol.Alcohol rapid draing, does not stay residue, this is with aesthetic benefits And facilitate the drying of skin.It is particularly interesting that ethyl alcohol (ethyl alcohol).
Ethyl alcohol has the beneficial property of several compositions for use in the present invention, including antimicrobial acivity, transdermal penetration Enhancing and rapid evaporation.Ethyl alcohol is a kind of well-known antimicrobial, is widely used in skin degerming.In addition, ethyl alcohol is inclined to In making skin dehydration, this can produce the environment for being unfavorable for fungi growth.In certain embodiments of the invention, medium can be limited The amount of middle ethyl alcohol is over-drying to may cause stimulation to prevent skin over-drying.Ethyl alcohol also as its rapid evaporation and it is advantageous, Rapid evaporation makes it more pleasant than other dermatology media for slowly drying or leaving residue.Even if ethyl alcohol has The tendency for generating burning sensation, is familiar for the people on notch using medicinal alcohol or after shaving using aftershave lotion , its benefit is also greater than this disadvantage.
Used the medium based on ethyl alcohol for the research report of tinea pedis from patient about the few of burning sensation Complain.(TRPV1) cationic channel of transient receptor potential vanillic acid 1 is sent the threshold value for showing the signal of overheat by ethyl alcohol to brain Temperature is reduced to 34 C from about 42 C.This new threshold temperature is lower than the core temperature of 37 C, therefore normal body temperature is led TRPV1 is caused to generate burning sensation.However, average foot temperature is between 30 C and 34 C, therefore it is experienced by ethyl alcohol to be applied to foot Burning sensation is minimum.
Transdermal penetration can be enhanced in studies have shown that ethyl alcohol.In vivo study shows compared with isopropyl myristate solution, Percutaneous Terbinafine is absorbed enhances (Alberti et al., International Journal of in ethanol solution Pharmaceutics, volume 219, page 11,2001).In addition, improvement has been displayed in ethyl alcohol gel compared with standard emulsifiable paste preparation Absorptivity, maximum concentration and half-life period (James et al., the Journal of of Terbinafine in skin Dermatological Treatment, volume 18, page 163,2007).Compared with emulsifiable paste, this enhancing allows to reduce Therapeutic frequency and/or duration for the treatment of.
Medium may include other component to enhance different qualities of the invention.Stabilizer or preservative, which is added, to be improved Stability of the invention.Similarly, solvent such as water and propylene glycol and surfactant can help solution to keep fine dispersion.It is fragrant Material can improve aesthetic qualities of the invention.Other compositions can be added in medium to slow down the release of active constituent, permit Perhaps the infiltration of application or increase active constituent less frequently.
Emollient (including silicone, oil, pure and mild vaseline) can be used for improving experience quality and reduce over-drying risk； However, it is necessary to select these ingredients advisably to avoid expection desiccation of the invention is offset.Medium based on emulsifiable paste is fitted The previously failure to the antiperspirant treatment of tinea pedis may be partially attributable to by obtaining its anti-moisture-keeping function, including be carried out by Koca et al. The research of clotrimazole-chlorination hydroxyl aluminium combination treatment.The treatment used in this research has had been acknowledged Railway Project.Due to suffering from Person is applied twice per day, and the moisturizing emulsifiable paste medium that Koca is used inhibits the crucial desiccation of antiperspirant.In addition, anti-with other Epiphyte pharmaceutical is compared with antiperspirant, and the specific antifungal agent and antiperspirant used is poor to the validity of tinea pedis.This research is foot The antiperspirant treatment of tinea has previously been confirmed as another reason invalid to tinea pedis.In fact, in Crawford & Hollis To in the systematicness comment of tinea pedis local treatment, Koca research is even excluded except consideration, because experiment reagent includes only Sweat agent.
The form and its application of composition
Active constituent (i.e. antifungal agent and antiperspirant) and various media can be delivered to skin in many different forms.The present invention Exemplified composition include liquid solution, spray, solid bar, gel, film forming solution, ointment, liquid bath, powder, lotion and Emulsifiable paste.The preferred embodiments of the invention include or use ethyl alcohol as solvent medium.Due to its increased dried active, ethyl alcohol Better than based on oil and based on the cream preparation of water.Liquid form can by physical feeling appropriate (such as foot) wipe or Friction is applied by the way that physical feeling is taken a shower in the solution.Spray can be with Direct spraying on the skin.Solid bar can be with Applied using the fricting movement on skin.Powder can be sprinkling upon in shoes before a pair of shoes is put on, or directly be sprinkling upon skin On skin.In addition, the compound can mix wherein during the manufacture of clothes product.In all cases, this hair should be applied It is bright so that active constituent reaches impacted region.In some embodiments, the present invention is applied to the bottom and side of both feet. This technology of studies have shown that can be effectively prevented to infect again, because fungi may unawares infect other portions of foot Position, and original infected zone is transferred back in untreated later.It is expected that composition of the invention can be applied at room temperature Foot.The composition should be applied to clean and dry foot.In one embodiment, composition applies before sleeping.
Activity component concentration be can choose to deliver the most effective treatment with best safety overview.Antimycotic component can be with The concentration for rising solution with about 0.1% to 20%, i.e., 1 to 200gm/ uses.There is preferred embodiment the spy no more than 10% to compare naphthalene It is fragrant.Antiperspirant can be used with the concentration (i.e. every liter of solution no more than about 300 grams of AlCl3) of the AlCl3 of about 0.1% to about 30%. In preferred embodiments, antifungal agent (Terbinafine) with about 1% concentration exist, antiperspirant (Aluminium chloride hexahydrate) with The concentration of about 15-20% exists.It is its for facilitating factor that composition of the invention, which is adjusted, to treat moisture caused by wherein sweat His microorganism infection, such as foot, armpit or inguinal bacterium and fungal infection.
Compared with the existing treatment of dermatomycosis, remarkable advantage of the invention is therapeutic frequency reduction.Existing treatment The main reason for treatment failure first is that bad abides by.Because applying oily cream twice daily is inconvenient and discomfort, Patient can stop treatment before successful eradication fungi.Due to combination treatment synergistic effect so that active constituent than it is any its Itself is more effective, can carry out treatment less frequently.Applying once a day is standard scheme of the invention, but even can be with Carry out less frequent treatment.Patient is more likely to abide by less cumbersome treatment schedule, therefore with successful eradication fungi of the present invention A possibility that it is bigger.
Cleaning piece embodiment
Embodiment of the present invention applies a composition to the impacted region of skin using disposable wipe, this is to control Treat the Novel Delivery mechanism of tinea pedis.This new part, which applies, represents the essential step advanced in tinea pedis treating, wherein most Treatment failure be due to patient complies and non-treatment it is invalid (de Chauvin et al., Mycoses, volume 51, page 1, 2007).Cleaning piece embodiment assists, cleans and facilitates aspect to provide benefit in dosing.
Material and manufacture
In a preferred embodiment, cleaning piece is Disposable, nonwoven polyester-viscose blend, than individual polyester More absorbability.Can be used artificial and/or natural fiber any combination, but warn the formula that may need to adjust solution or Volume is to ensure the appropriate delivering of active constituent.For example, the poor 100% polyester cleaning piece of absorbability may be needed with more concentrated Solution saturation to deliver the active constituent of suitable dosage.Pharmacokinetics tests the active constituent that can be used for ensuring suitable dosage Successful deposition is on the skin.
Untreated cleaning piece can be folded and inserted into individual pouch (they seal in three faces and open in side). Pouch can be the metal laminate polyethylene that there is recess in side can easily tear.Other individual sachet materials are also possible , including layers of foil platen or no lamination polyethylene.Alternatively, cleaning piece can wrap in the container of resealable rather than single In only pouch.In this case, it will need to prepare solution to ensure that all cleaning pieces keep appropriate saturation.
Liquid solution containing active constituent is added in pouch, and by pouch in its side seal that is open.If desired, can To apply pressure to pouch to ensure that entire cleaning piece is sufficiently saturated.Packaging process can be completed by packing machine, or can be It is completed when needing a small amount of by hand.
Apply
In order to use cleaning piece, to open it, cleaning piece should be unfolded for the end for the packaging that should tear, and patient should be wiped by hand Wipe any impacted region.Between toe in the case where tinea pedis, patient should thoroughly wipe each Interdigital Space.In some embodiment party In case, the bottom and side of both feet should be wiped.Studies have shown that the technology is effective in preventing from infecting again, because fungi may not Know other positions for unconsciously infecting foot, and original infected zone can be transferred back in untreated later.Cleaning piece can be with Two cleaning pieces being packaged as in pouch, one or one cleaning piece of every foot can be used for both feet, as long as saturation degree is suitable for Apply.
The benefit of cleaning piece embodiment
Dosing auxiliary
In some embodiments, compared with emulsifiable paste, gel or spray, disposable wipe, which applies, to be provided to patient's dosing A greater degree of control.It may be using very little (causing drug delivery insufficient) or too much (before leading to treatment end with wherein patient It is treated supply and is finished) conventional local treatment it is different, the cleaning piece individually packed provides correct agent with minor error possibility The active constituent of amount.The method of tinea pedis treating is typically due to be stopped treating and failing too early by patient at present, once its disease of patient Shape subsides but may stop using local treatment before infection completely eliminates.It can be using the composition that cleaning piece is invented Discontinuous amount (for example, 28 individually packet be used for 4 weeks treatment process) rather than one have the dosage for not knowing quantity Pipe in pack；Therefore, patient may more likely abide by complete therapeutic scheme.Embodiment of the present invention includes having 7 Or 14 packet (such as cleaning piece) packaging, it is contemplated that duration for the treatment of be one week or two weeks.Daily administration is preferably, with minimum Change therapeutic value that is over-drying, and providing required simultaneously.It has been found that this includes antifungal agent, antiperspirant and desiccant Application no matter treat start when disease stage how to be all effective in the treatment.
Disposable wipe can also be with false impulse therapy.For example, in 4 weeks antifungal agent-antiperspirant combination treatments, When still applying antifungal agent daily, it may be beneficial for reducing being applied to for antiperspirant twice a week.Trouble can be supplied to Person 28 mark the individual pouch having for daily appropriate drug for having the date used, rather than require patient Which day which keep that drug application tracked.This enables the patient to easily apply correct medicament, and increases and abide by full treatment A possibility that process.
Cleaning action
Disposable wipe, which applies, utilizes friction --- clean the important composition on any surface.When patient is not in direct contact with the skin When, patient tends to more effectively apply friction.This is partly due to the natural lubrication of the oil on skin, and is partly due to pair Deeply excavate the intelligible hesitation of infected area.In addition, disposable wipe be applied through hand and infected foot it Between provide barrier to reduce the risk of unexpected manual transmission, this reduces the hesitation of patient when applying medicament, increases application It rubs and therefore cleans infected skin.
It is convenient and comfortable
Many existing topical antifungal agents apply, especially topical cream, leave oiliness residue on the skin.Many patients It was found that this makes us uncomfortable, especially when they need shortly to put on socks and shoes after the application.Because cleaning piece allows Drug delivers in liquid solution, rather than needs semisolid emulsion as emulsifiable paste or gel, can use in liquid form Solvent such as ethyl alcohol.Ethyl alcohol is a kind of preferred medium, because it is evaporated rapidly, generates refrigerant sense, and make to have dry skin.It is many This experience that patient feels pleasure facilitates ethyl alcohol popularizing in other topical products, including hand cleanser and aftershave lotion.Together Sample, by using ethyl alcohol, composition will not leave on hand oiliness residue.In addition, ethyl alcohol causes calcination when being applied to foot The trend of sense minimizes, because the temperature of foot (sees above in " medium " part ethyl alcohol to TRPV1 lower than the other parts of body Effect complete explanation).
Patient's non-compliance is the significant obstacle of effective treatment tinea pedis, and composition of the invention improves the comfortable of patient Degree, and significant improvement therefore is provided compared with existing treatment, because patient compliance increases.Open packaging, wiping foot and The simple procedure for abandoning cleaning piece, which has imitated, uses the experience of being familiar with of wet towelette on hand in dining room, and lacks on hand and foot The residue left means that patient will tend to continual cure and be longer than their otherwise possible times.
Embodiment 1- uses the exemplary test results of composition of the invention
The preliminary test that embodiment of the present invention is carried out to the patient with tinea pedis, by application once a day of the invention and mesh The standard care (twice daily applying terbinafine emulsifiable paste) of preceding tinea pedis and placebo are (by the towelette group being saturated with ethyl alcohol At, but both without antifungal agent or be free of antiperspirant) compare.The results of the study show that with treatment once a day of the invention For similarly effective with the twice daily treatment of terbinafine emulsifiable paste, and it is more significant than placebo more effective.Every kind of method treatment 30 (30) name patients, it is for 4 weeks, and 2 weeks record results after treatment is finished.Use depositing for potassium hydroxide preparation test fungi ?.At the end of the research, with compared with 22 patients that terbinafine emulsifiable paste is treated, 21 have with the patient that the present invention treats There are negative findings.At the end of the study, only 8 are negative with the patient of placebo treatment.Subjective feedback from patient has Conducive to the present invention.Emulsifiable paste is described as " smooth " and " uncomfortable ", and twice daily applies and be described as " bothering ", and of the invention It is described as " being very easy to use " and " highly effective ".One patient says, it is seen that the present invention can be with commercial exploitation, she will " wild with joy ", and another one patient declares at the end of the study, this is " the once locating optimum state of my foot ".
Negative KOH after table 1:6 weeks
Treatment Patient numbers with negative KOH
It invents (1x/day) 21/30
Terbinafine emulsifiable paste (2x/day) 22/30
Placebo (1x/day) 7/30
These results of study show to apply once a day of the invention similarly effective with twice daily application terbinafine emulsifiable paste. This increased convenience is particularly pertinent because it is undesirable treatment abide by property be tinea pedis treating in practice why the master for Shi Baiing Want reason.The treatment for needing less frequently to apply is more likely to be used for entire treatment phase, and is therefore more likely to treat wherein more may be used The reality that can stop generates positive result in applying.The active responding of patient for treatment also indicates that treatment will be controlled than current standard Treat more preferable receive.Relative to oily cream, patient prefers dry feeling of the invention, and this experience preference will further change The kind property abided by, and therefore improve result.
Select the researching and designing with consistent with for the standard clinical tests of antifungal therapies of tinea pedis, standard clinical examination It tests using 4 weeks treatment process and needs to confirm fungal infection.As discussed before, this, which eliminates fungal infection and has been infected by bacterial, takes The patient in generation.For these patients, the present invention may be significantly more more effective than individual antifungal agent.
Embodiment 2- is used to manufacture the illustrative methods of composition
Ethyl alcohol is added in container, the volume of ethyl alcohol is no more than the 75% of required final volume.Terbinafine powder is added to In container and stir.The quality that Terbinafine is added makes the concentration of Terbinafine will be molten for every liter under required final volume About 10 grams of liquid.Crystallization Aluminium chloride hexahydrate is added into solution, so that concentration is about 200gm/ liter under required final volume Aluminium chloride.Crystallization Aluminium chloride hexahydrate can crush before addition, so that dissolution can be faster.By Terbinafine and six chloride hydrates After aluminium is added to solution, more ethyl alcohol are added until volume reaches required final volume.Sealing container to prevent from evaporating, and Solid component is dissolved to generate uniform solution.Heating and stirring can be introduced to accelerate course of dissolution.Cleaning piece can be with molten Liquid saturation is for patient's application.
Embodiment 3- uses treatment and cost savings of the invention
In certain embodiments, such as the present invention is applied directly to foot by spray or gel, patient.In these cases, The present invention has the potentiality saved than existing treatment cost, resists very because being reached with treatment once a day of the invention with standard Microbial inoculum twice daily treats identical effect.The production of the antiperspirant component in the present invention is added to than needed for twice daily treatment Additional quantity antifungal agent it is more cheap.In addition, patient is less because the present invention can be happier and more effective than existing treatment It may stop treating and undergoing the recurrence of infection in advance, and need other treatment.The re-treatment of this redundancy is treatment tinea pedis In important cost, and reduce through the invention.
The consistent treatment of embodiment 4-, no matter the stage of infection
Compared with existing tinea pedis treating, it is one advantage of the present invention that how its stage no matter infected all treats the energy of infection Power.As previously mentioned, the simple form (pure dermatomycosis) of the disease is pure fungal infection, it is characterised in that dry Dry, squamous skin.When bacterium is proliferated in infected space, replaces fungi, it is multiple which is referred to as dermatomycosis Zoarium, and it is characterized in that more make us uncomfortable symptom, especially macerates and smell.In this stage of the disease, individually Antifungal agent effect is poor, because of the main reason for bacterium has become in infection.It is not universal to the understanding of this difference, and disease Two stages of disease are considered as " tinea pedis "；Therefore, infection, which will proceed to the people in dermatomycosis complex stage, will seek The common treatment to tinea pedis, such as over the counter topical antifungal agents emulsifiable paste are asked, the stage of disease is less likely effective.It can It can need unsuccessful treatment several times, dermatologist and laboratory work is met correctly to identify and treat infection.
The present invention is advantageous, because it is effective to the tinea pedis in any developing stage.Antifungal agent eliminates fungi, only Sweat agent and alcohol medium have an antibacterial activity, and the sweat blocking activities of antiperspirant and the desiccation of alcohol cause to be unfavorable for fungi and The dry environment of bacterial growth.Therefore, patients and clinicians can be benefited from a kind of be effective against in the treatment of tinea pedis no matter The needs of a possibility that how is infective stage, which reduces futile treatment and the diagnostic test that determination is correctly treated.
The treatment of the various dermatomycosis of embodiment 5-
The present invention is promising due to its ability for being used to treat various forms of dermatomycosis.It has been discussed in detail herein Tinea pedis, but antifungal agent-antiperspirant combination treatment benefit extends to the dermatophyte that other sweat may be aggravation factor Disease.Jock itch (Tinea cruris, jock itch) influence groin, due to be blocked for clothes trapping moisture and heat, this It is an ideal fungi growing environment.Ringworm of the body (tinea) usually influences the region of wherein sweat accumulation, such as armpit and abdomen skin Skin gauffer.Other dermatomycosis, including the tinea manuum, it is more common in the crowd of excessive sweating.Sweat is fungi sense wherein In all these situations of hair dyeing exhibition and lasting existing contribution factor, antifungal agent-antiperspirant treatment is advantageous.By subtracting Hypohidrosis liquid, it inhibits to be conducive to the condition of fungi growth, and it assures success to the activity of broad-spectrum micro-organisms and treats fungal infection With any opportunistic coinfection being likely to occur in the cuticula of weakening.
Although the present invention is specifically illustrated and described by reference to specific preferred embodiment, those skilled in the art should Understand, it, wherein can be in shape in the case where not departing from the spirit and scope of the present invention such as defined by appended claims Various changes are carried out in formula and details.
I claims according to right.

Claims (28)

1. a kind of method for treating dermatophytid infection, comprising the following steps:
Part applies antifungal agent；
Part applies the antiperspirant containing aluminium salt；
Part applies the solvent medium comprising alcohol,
Wherein the antifungal agent, the antiperspirant and the solvent medium all apply during single administration event；With
The application event is repeated to be no more than once a day.
2. the method for claim 1 wherein the antifungal agent is the fungicide containing allylamine.
3. method for claim 2, wherein the antifungal agent is Terbinafine or its pharmaceutically acceptable salt.
4. the method for claim 1 wherein the antifungal agent is fungicide, including Amorolfine, Butenafine, naphthalene replace Fragrant, Terbinafine or at least one of Tolnaftate or its pharmaceutically acceptable salt.
5. such as being tested by KOH microscope can the method for claim 1 wherein the application is repeated until the infection solves Measurement.
6. the method for claim 1 wherein the antiperspirant is Aluminium chloride hexahydrate.
7. the method for claim 1 wherein the solvent mediums to be substantially made of ethyl alcohol.
8. the method for claim 1 wherein the duration for the treatment of is 1-4 weeks.
9. the method for claim 1 wherein the antifungal agent includes at least one below: azole, including clotrimazole, ketone health Azoles, Fluconazole, Flutrimazole, econazole, bifonazole, butoconazole, econazole, Fenticonazole, Isoconazole, luliconazole, Miconazole, Omoconazole, Oxiconazole, Sertaconazole, sulconazole, tioconazole, thiabendazolum, croconazole, benzyl chloride reach azoles, Nai Kang At least one of azoles, terconazole, posaconazole, voriconazole, albaconazole, Chinese mugwort Saperconazole, Eberconazole or Chinese mugwort Fluconazole； Or at least one of polyenoid, including amphotericin B, nystatin, Hamycin and natamycin；Or nystatin, natamycin, song First between ancient mycin, pecilocin, mepartricin, pyrrolnitrin, griseofulvin, Bromosalicylchloranilide, methylrosaniline, tribromo Phenol, undecenoic acid, polynoxylin, 2- (4- chlorophenoxy)-ethyl alcohol, Chlorphenesin, Ticlatone, Afungin, to hydroxyl Yl benzoic acid ethyl ester, Haloprogin, selenium sulfide, Ciclopirox Olamine, dimazole, Flucytosine, benzalkonium chloride, benzoyl peroxide, Benzoic acid, salicylic acid, tannic acid, boric acid, gentian violet, Chlorhexidine, cetylpyridinium chloride, tolciclate, sodium thiosulfate, iodine Change potassium, tea oil, citronella oil, lemongrass oil, garlic, vinegar, he cut down boron sieve, Abafungin, echinocandin (Caspofungin, meter Ka Fragrant net and anidulafungin), Nikemycin, at least one of pradimicin or Bei Nanuo mycin；Or its is pharmaceutically acceptable Salt.
10. a kind of composition of effectively treatment dermatophytid infection, the composition includes:
Antifungal agent；
Hidroschesis desiccant containing aluminium salt；With
Solvent medium without emulsifiable paste, the solvent medium includes alcohol, for delivering antifungal agent and desiccant.
11. method for claim 10, wherein the antifungal agent is fungicide.
12. the method for claim 11, wherein the antifungal agent is Terbinafine or its pharmaceutically acceptable salt.
13. the composition of claim 10, wherein the antifungal agent is fungicide, including Amorolfine, Butenafine, naphthalene For fragrant, Terbinafine or at least one of Tolnaftate or its pharmaceutically acceptable salt.
14. a kind of cleaning piece, it includes the composition of claim 10, the cleaning piece is used to be applied to and treat the skin of patient Skin fungal diseases.
15. the composition of claim 12, wherein the Terbinafine exists with the amount of the 0.5-10% of composition weight.
16. the composition of claim 10, wherein the aluminium salt exists with the amount of no more than about 30% weight.
17. the composition of claim 16, wherein the aluminium salt exists with the amount of 15-20% weight.
18. the composition of claim 10, wherein the antiperspirant is AlCl3•6H2O。
19. it is a kind of for treating the solution of dermatophytid infection, it is generated by following procedure:
Terbinafine is added in the liquid solvent solution comprising ethyl alcohol；
By the crushing crystalline A lCl through measurement amount3•6H2O is added in solution；
Make-up solution is added in case of need, with establish about 200 grams per liter solution AlCl3.6H20 concentration and about 10 grams/ Rise the terbinafine concentration of solution；With
The Terbinafine and the AlCl3 are dissolved to provide uniform solution.
20. the solution of claim 19, wherein the solution is distributed on cleaning piece for treating the dermatophyte illness of patient.
21. the solution of claim 19, wherein the Terbinafine is powder.
22. the solution of claim 19, wherein the Terbinafine is added with the amount of no more than about 100 grams per liters.
23. the solution of claim 19, wherein AlCl3It is added with the amount of no more than about 300 grams per liters.
24. a kind of for treating the kit of dermatophyte illness, comprising:
Product, the product includes:
Containing can the amounts of about 200 grams per liters be dissolved in the antiperspirant of the aluminium salt in alcoholic solvent,
The fungicide in the solution is dissolved in,
Alcoholic solvent, antiperspirant and fungicide dissolve in the alcohol to form solution；With
For accommodating the storage container of at least one product.
25. the kit of claim 24, wherein the fungicide includes that orolfin, Butenafine, Naftifine, spy compare naphthalene Fragrant or at least one of Tolnaftate or its pharmaceutically acceptable salt.
26. the kit of claim 24, the kit further includes applicator, and the applicator includes cleaning piece or spin.
27. the kit of claim 24, the kit includes the cleaning piece that at least seven is used to apply the solution.
28. the kit of claim 24, further includes calendar and instruction set, the calendar is used to track using the kit The daily administration for the treatment of.
CN201780066597.1A 2016-08-29 2017-08-22 For treating the method and composition of dermatophytid infection Pending CN109862882A (en)

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JP2019526631A (en) 2019-09-19
AU2017320876A1 (en) 2019-03-07
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WO2018044621A1 (en) 2018-03-08

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